Subscribe Now Subscribe Today
Research Article
 

Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia



Samar A. Damiati and Samir M. Khoja
 
Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail
ABSTRACT

In this study we aimed to determine the effect of gender differences on serum asymmetric dimethyl-l-aiginine (ADMA) levels in renal failure patients. Serum ADMA concentrations and other factors were measured in 59 subjects, 25 control subjects (males/females 13/12) and 34 patients with renal failure (males/females 16/18). Patients attended Nephrology Department in King Abdulaziz University Hospital (Jeddah, Saudi Arabia) between December 2009 and February 2010. ADMA concentrations were measured by competitive ELISA. The serum concentrations of ADMA were significantly elevated in patients with renal failure when compared with their matched control subjects in both sexes. In males, the Mean±SD concentration of ADMA was 1.49±0.18 vs. 0.62±0.23 μmol L-1 (p<0.001). In females, ADMA concentrations were 1.31±0.27 vs. 0.59±0.16 μmol L-1 (p<0.01). In patients with renal failure, ADMA concentrations were significantly decreased in females as compared with males (1.31±0.27 vs. 1.49±0.18 μmol L-1, p<0.05). There was no significant difference in serum ADMA concentration in control male and female subjects. Thus, the present available data suggested that accumulation of ADMA showed gender differences in renal failure patients, which probably contribute to a higher risk of cardiovascular diseases and total mortality in males.

Services
Related Articles in ASCI
Search in Google Scholar
View Citation
Report Citation

 
  How to cite this article:

Samar A. Damiati and Samir M. Khoja, 2011. Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia. Trends in Medical Research, 6: 14-22.

DOI: 10.3923/tmr.2011.14.22

URL: https://scialert.net/abstract/?doi=tmr.2011.14.22
 
Received: October 02, 2010; Accepted: January 15, 2011; Published: May 06, 2011



INTRODUCTION

Cardiovascular complications are a major clinical problem in patients with renal failure; cardiac death accounts for approximately 40-50% of all deaths in these patients. Death from cardiovascular causes is up to 20 times more common in uremic patients than in the general population with the risk being even higher than in patients with diabetes mellitus (Campean et al., 2005). One pathogenic mechanism that might contribute to cardiovascular risk in these patients is endothelial dysfunction. Endothelial dysfunction is characterized by reduced bioactivity of the anti-atherogenic molecule Nitric Oxide (NO) and is considered a proatherogenic condition (Cross et al., 2001; Mittermayer et al., 2005; Kawashima and Yokoyama, 2004; McGrowder et al., 2006).

NO is the most potent endogenous vasodilator known, synthesized from L-arginine by the action of a family of NO synthase (NOS) with endothelial, neural and macrophage isoforms (Cooke, 2000; Kielstein et al., 2001a; Lokhande et al., 2006). Synthesis of NO can be selectively inhibited by asymmetric dimethyl-L-arginine (ADMA), a methylated L-arginine derivative, which act as a competitive inhibitor at the active site of the enzyme (Zinellu et al., 2007; Brooks et al., 2009).

ADMA is produced by catabolism of proteins containing methylated arginine residues via protein arginine methyl transferases and subsequently hydrolyzed (Vallance and Leiper, 2004). ADMA is eliminated in part by renal excretion. Reduced clearance of ADMA in renal failure is associated with endothelial vasodilator dysfunction, reversible by administration of L-arginine (Vallance and Leiper, 2004; Kielstein et al., 2001b), or by dialysis (Boger and Zoccali, 2003). Free ADMA actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH metabolizes ADMA to L-citrulline and dimethylamine (Teerlink, 2005; Murray-Rust et al., 2001).

Accumulation of ADMA has been linked to endothelial dysfunction in many diseases and repeatedly associated with kidney failure. ADMA is markedly increased in patients with renal failure, partly because of reduced renal excretion and may contribute to their excess cardiovascular event rate (Mittermayer et al., 2005; Boger and Zoccali, 2003). Thus ADMA may be regarded as a uremic toxin (Kielstein et al., 2001a).

High serum ADMA concentrations in renal failure patients may contribute to acceleration of cardiovascular disease and total mortality in this patient population (Boger and Zoccali, 2003; Zoungas et al., 2006).

Endothelial dysfunction and reduced NO bioactivity occur in patients on haemodialysis, peritoneal dialysis and in those with chronic renal failure prior to the introduction of renal replacement therapy (Cross et al., 2001; Tepel et al., 2003). ADMA concentration elevated in dialyzed patients and decreased by dialysis (Boger and Zoccali, 2003). More than one-half of all dialysis-related deaths are cardiovascular in nature (Karnik et al., 2001).

Since, males have a higher risk of cardiovascular diseases, the leading cause of mortality in patients with renal failure, than females; that may be due to the accumulation of ADMA in uremic males. The present study was carried out to clarify whether gender differences affect ADMA levels in renal failure patients.

MATERIALS AND METHOD

Subjects: The present study was carried out on two groups of individuals: twenty-five control subjects (13 males, 12 females); aged between 19 and 70 years and thirty-four uraemic subjects (16 males, 18 females); aged between 15 and 73 years; only 25 patients undergoing dialysis. Samples were collected from the patients during their visit to Nephrology Department in King Abdulaziz University Hospital (Jeddah, Saudi Arabia) during the period December 2009 to February 2010. A letter of consent was taken from the patients approving the collection of the samples.

Biochemical analysis: Serum ADMA levels was determined by competitive ELISA (DLD Diagnostika GmbH, Hamburg, Germany).

Sample preparation: Sample acylation was conducted in the 96-well reaction plate supplied with the kit according to the instructions of the manufacturer. Standards, kit controls and samples (20 μL) were mixed with 25 μL acylation buffer and 25 μL equalizing reagent. Subsequently, 25 μL acylation reagent was added and the reaction plate was incubated for 30 min at room temperature on an orbital shaker. Diluted equalizing reagent (100 μL) was added and the reaction plate was again incubated for 45 min. After the incubation, the samples were ready for the ELISA analysis.

Performance of assay: The ADMA-ELISA kit consists of a split-type reaction plate (12x8) coated with ADMA, six standards (0-5 μmol L-1), rabbit anti-ADMA antiserum, goat anti-rabbit-IgG-peroxidase conjugate, TMB substrate solution, stop solution and wash buffer. Aliquots (50 μL) of the acylated standards, kit controls or samples were processed according to the instructions of the kit manufacturer. Absorbance was read at 450 nm (reference wavelength 570-650 nm) using microplate photometer within 1 h. All samples, kit controls and standards were analyzed in duplicate.

Determination of clinical parameters: Serum creatinine and Blood Urea Nitrogen (BUN) were measured by using specific Flex reagent cartridges (Siemens Healthcare Diagnostics Inc., Newark, USA) on a Dimension clinical system (DADE Behring Inc., Newark, USA). Cholesterol and triacylglycerol (TAG) were determined by enzymatic analysis, according to the manufacturer's protocol (SPINREACT, Spain) using a spectrophotometer (Jenway 6305, UK).

Determination of creatinine: In the presence of a strong base such as NaOH, picrate reacts with creatinine to form a red chromophore. The rate of increasing absorbance at 510 nm due to the formation of this chromophore is directly proportional to the creatinine concentration in the sample and is measured using a bichromatic (510, 600 nm) rate technique. Bilirubin is oxidized by potassium ferricyanide to prevent interference (Knapp and Mayne, 1987).

Determination of Blood Urea Nitrogen (BUN): Concentration of BUN was determined by using a bichromatic (340 nm) rate technique (Dafoe et al., 2008).

Determination of cholesterol: The cholesterol present in the sample originates a colored complex, according to the following reaction:

Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia

The intensity of the color formed is proportional to the cholesterol concentration in the sample (Natio and Kaplan, 1984; Meiattini et al., 1978).

Determination of TAG: TAG is measured according to the following reaction:

Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia

The intensity of the color formed is proportional to the triglycerides concentration in the sample (Bucolo and David, 1973; Fossati and Prencipe, 1982).

Statistical analysis: The data are expressed as Means±SD comparison between mean of two groups was performed using independent-sample t-test. Statistically significant results were considered at p<0.05 or less. Pearson correlation coefficients (r) were used to assess the significance of the association of ADMA with serum creatinine, BUN, Cholesterol and TAG. The statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL), version 12.0 for windows.

RESULTS AND DISCUSSION

Table 1 shows clinical data of control and renal failure subjects. Control and uremic subjects were well matched for age. Mean serum ADMA concentration was significantly higher in patients than in control subjects in both sexes. In uremic males, ADMA concentrations was 1.49±0.18 vs. 0.62±0.23 μmol L-1 in the control (p<0.001) and 1.31±0.27 vs. 0.59±0.16 μmol L-1 (p<0.01) in females subjects. Significant increases in serum cholesterol, creatinine and urea were observed in the males with renal failure when compared with control (cholesterol: 3.26±1.82 vs. 2.12±0.76 mmol L-1 (p<0.05); creatinine, 500.88±280.18 vs. 79.69±20.11 μmol L-1 (p<0.001); urea, 18.84±11.32 vs. 4.46±1.39 mmol L-1 (p<0.001)). In females, significant increases were found in the concentrations creatinine and urea (creatinine: 455.50±165.47 vs. 55.83±14.18 μmol L-1 (p<0.001); urea, 11.93±7.87 vs. 3.64±2.25 mmol L-1 (p<0.001)). There were no significant associations among age and TAG in both sexes.

Male subjects show higher serum ADMA levels than female subjects. In patients with renal failure, ADMA concentration was significantly decreased in females as compared with males (1.31±0.27 μmol L-1 vs. 1.49±0.18 μmol L-1, p<0.05). There was slightly but not significantly increases in ADMA level in control males than females.

Correlations of factor potentially associated with ADMA in renal failure patients are showed in Table 2. In males with renal failure, a positive correlation were found between serum ADMA and cholesterol (r = 0.524, p<0.05), creatinine (r = 0.541, p<0.05, Fig. 1) and urea (r = 0.508, p<0.05, Fig. 2a). No correlations were found with age or TAG. In uremic females, ADMA was inversely correlated with cholesterol (r = 0.498, p<0.05) and urea (r = -0.591, p<0.01, Fig. 2b). No correlations were found between ADMA and age, TAG or creatinine.

Table 1: Clinical characteristics of subject studies
Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia
Results are expressed as Mean±SD, with (n) is the number of subjects. Significant differences between control and other groups are shown as: * = p<0.05, *** = p<0.001, ns: non-significant

Table 2: Bivariate analysis of factor potentially associated with ADMA in renal failure patients
Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia
*Correlation is significant at 0.05 level (2-tailed). **Correlation is significant at 0.01 level (2-tailed), ns: non significant

Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia
Fig. 1: Correlation analysis between ADMA levels and creatinine in male patients with renal failure

Image for - Serum Asymmetric Dimethyl-L-Arginine in Renal Failure Patients Living in Jeddah Region, Saudi Arabia
Fig. 2: Correlation analysis between ADMA levels and urea in (a) male and (b) female patients with renal failure

The results of this study demonstrate that sex-dependent differences were found in serum ADMA concentration in controls and uremic patients, ADMA concentrations were significantly higher in patients with renal disease compared with matched controls, increased serum creatinine levels associated with increased levels of ADMA in uremic males and elevated levels of ADMA might contribute to greater risk for cardiovascular diseases in uremic males than females.

ADMA correlated with several risk factors in the absence of clinical disease (Miyazaki et al., 1999). It is predictive for the all over mortality and cardiovascular outcome in renal failure patients. The mortality rate in these patients is 10%/yr (Zoccali et al., 2001). ADMA are markedly increased at a very early stage of renal failure, even when Glomerular Filtration Rate (GFR) is still within the normal range (Kielstein et al., 2002).

There is substantial agreement that the plasma concentration of ADMA is higher in patients with uremia than in subjects with normal renal function (Vallance et al., 1992; MacAllister et al., 1996; Kielstein et al., 1999; Zoccali et al., 2001, 2002). In this study, control males had non significant increase in serum ADMA levels when compared to females. In patients with renal failure, males showed significantly higher ADMA levels than females. This may explain why men are at great risk for coronary heart disease (Fodor and Tzerovska, 2004; Rgitz-Zagrosek et al., 2006).

The accumulation of endothelial toxins in uremia could contribute to the impaired NO-mediated dilatation reported in renal failure patients (Vallance et al., 1992). NO deficiency due to inhibited production by ADMA, impairs cardiac function and increases peripheral vascular resistance (Lin et al., 2002; Kielstein et al., 2004; Achan et al., 2003). Thus, ADMA is a biologically active NOS inhibitor with a long duration of action (Fliser et al., 2005). Chronically elevated ADMA blood levels may promote progression of renal (vascular) disease via endothelial damage as a consequence of reduced NO availability (Fliser et al., 2005; Erdely et al., 2003; Kang et al., 2002). The high incidence of hypertension and atherosclerosis encountered in patients with terminal renal failure might be caused by accumulation of ADMA as a result of reduced renal excretion which is sufficiently high to reduce significantly NO production (Vallance et al., 1992; Xiao et al., 2001).

In this study the mean age for females (control: 43.50±26.81, uremic: 40.67±20.44 years) was younger than males (control: 53.69±18.38, uremic: 54.75±22.60 years) and females showed lower serum ADMA levels than males. This result was in agreement with other published data (Damiati and Khoja, 2009; Schulze et al., 2005) which found sex-dependent differences between ADMA and age. Females younger than 50 years had lower serum ADMA levels than males but higher levels with the onset of menopause and this may be explained by differences in hormonal status.

In humans, approximately 300 μmol of ADMA is generated per day, approximately 250 μmol of which is metabolized by the enzyme DDAH, whereas only a minor amount is excreted unchanged by the kidneys (Achan et al., 2003). Metabolism of ADMA by DDAH may also be impaired in uremia (Kielstein et al., 1999; Kielstein et al., 2001b). DDAH is found in a variety of human tissues, including kidney, pancreas and human blood vessels (Najbauer et al., 1993; MacAllister et al., 1996). A high DDAH activity has been observed in the kidney (Leiper et al., 1999; Tran et al., 2000) which have reveled that the kidney is a major extraction site for ADMA from the circulation (Nijveldt et al., 2002). These data may explain why even minor renal dysfunction leads to accumulation of ADMA (Fliser et al., 2005).

In the presence of an increased serum creatinine and urea or a decreased GFR, morbidity and mortality because of CVD are markedly increased and vascular degradation is accelerated (Aronson et al., 2008; Vanholder et al., 2005). In this study, males had a higher serum creatinine and urea than females in control and uremic subjects. Males with renal failure showed a positive correlation between serum ADMA and creatinine (r = 0.541, p<0.05), urea (r = 0.508, p<0.05). Thus, increased levels of ADMA in males may relate to increased levels of serum creatinine and urea. In uremic females, unexpected result was obtained. There was no correlation between ADMA and creatinine and ADMA was inversely correlated with urea (r = -0.591, p<0.01).

In conclusion, accumulations of ADMA are correlated to gender differences in patients with renal failure. Thus, ADMA may be considered as an independent predictor of future cardiovascular events and total mortality in these patients.

REFERENCES

1:  Achan, V., M. Broadhead, M. Malaki, G. Whitley and J. Leiper et al., 2003. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylhydrolase. Arteroscler Thromb. Vasc. Biol., 23: 1455-1459.

2:  Aronson, D., H. Hammerman, R. Beyar, S. Yalonetsky, M. Kapeliovich, W. Markiewicz and A. Goldberg, 2008. Serum blood urea nitrogen and long-term mortality in acute ST-elevation myocardial infarction. Int. J. Cardiol., 127: 380-385.
PubMed  |  Direct Link  |  

3:  Boger, R. and C. Zoccali, 2003. ADMA: A novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosc. Suppl., 4: 23-28.
CrossRef  |  

4:  Brooks, E., C. Langman, S. Wang, E. Heather Price and L. Abigail et al., 2009. Methylated arginine derivatives in children and adolescents with chronic kidney disease. Pediatr. Nephrol., 24: 129-134.
CrossRef  |  Direct Link  |  

5:  Bucolo, G. and H. David, 1973. Quantitative determination of serum triglycerides by the use of enzymes. Clin. Chem., 19: 476-482.
PubMed  |  Direct Link  |  

6:  Campean, V., D. Neureiter, I. Varga, F. Runk and A. Reiman et al., 2005. Atherosclerosis and vascular calcification in chronic renal failure. Kidney Blood Press Res., 28: 280-289.
CrossRef  |  Direct Link  |  

7:  Cooke, J.P., 2000. Does ADMA cause endothelial dysfunction. Arterioscl. Thromb. Vasc. Biol., 20: 2032-2037.

8:  Cross, J., A. Donald, P. Vallance, J.E. Deanfield, R.G. Woolfson and R.J. MacAllister, 2001. Dialysis improves endothelial function in humans. Nephrol. Dial. Transplant., 16: 1823-1829.
CrossRef  |  Direct Link  |  

9:  Dafoe, J., R. Kott, B. Sowell, J.G. Berardinelli, K.C. Davis and P.G. Hatfield, 2008. Effects of supplemental safflower and vitamin E during late gestation on lamb growth, serum metabolites and thermogenesis. J. Anim. Sci., 86: 3194-3202.
CrossRef  |  Direct Link  |  

10:  Damiati, S. and S. Khoja, 2009. Asymmetric dimethyl-L-arginine in diabetes mellitus and hyperlipidemia. Clin. Exp. Med. J., 3: 443-452.

11:  Erdely, A., L. Wagner, V. Muller, A. Szabo and C. Baylis, 2003. Protection of wistar furth rats from chronic renal disease is associated with maintained renal nitric oxide synthase. J. Am. Soc. Nephrol., 14: 2526-2533.
PubMed  |  Direct Link  |  

12:  Fliser, D., F. Kronenberg, J. Kielstein, C. Morath, S.M. Bode-Boger, H. Haller and E. Ritz, 2005. Asymmetric dimethylarginine and progression of chronic kidney disease: The mild to moderate kidney disease study. J. Am. Soc. Nephrol., 16: 2456-2461.
PubMed  |  Direct Link  |  

13:  Fodor, J. and R. Tzerovska, 2004. Coronary heart disease: Is gender important. JMHG., 1: 32-37.
Direct Link  |  

14:  Fossati, P. and L. Prencipe, 1982. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin. Chem., 28: 2077-2080.
CrossRef  |  PubMed  |  Direct Link  |  

15:  Karnik, J.A., B.S. Young, N.L. Lew, M. Herget, C. Dubinsky, J.M. Lazarus and G.M. Chertow, 2001. Cardiac arrest and sudden death in dialysis units. Kidney Int., 60: 350-357.
CrossRef  |  

16:  Kang, D.H., T. Nakagawa, L. Feng and R. Johnson, 2002. Nitric oxide modulates vascular disease in the remnant kidney model. Am. J. Pathol., 161: 239-248.
Direct Link  |  

17:  Kawashima, S. and M. Yokoyama, 2004. Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 24: 998-1005.
Direct Link  |  

18:  Kielstein, J., R. Boger, S. Bode-Boger, J.C. Frolich, H. Haller, E. Ritz and D. Fliser, 2002. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J. Am. Soc. Nephrol., 13: 170-176.
PubMed  |  Direct Link  |  

19:  Kielstein, J., S. Bode-Boger, J. Frolich, H. Haller and R.H. Boger, 2001. Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease. Kidney Int. Suppl., 78: S9-S13.
CrossRef  |  Direct Link  |  

20:  Kielstein, J., R. Boger, S. Bode-Boger, J. Schaffer, M. Barbey, K.M. Koch and J.C. Frolich, 1999. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: Relationship to treatment method and atherosclerotic disease. J. Am. Soc. Nephrol., 10: 594-600.
PubMed  |  Direct Link  |  

21:  Kielstein, J., J. Frolich, H. Haller and D. Flisero, 2001. ADMA (asymmetric dimethylarginine): An atherosclerotic disease mediating agent in patients with renal disease. Nephrol. Dial. Transplant., 16: 1742-1745.
CrossRef  |  Direct Link  |  

22:  Kielstein, J., B. Impraim, S. Simmel, S.M. Bode-Boger and D. Tsikas et al., 2004. Cardiovascular effects of systemic Nitric Oxide synthase inhibition with asymmetric dimethylarginine in humans. Circ., 109: 172-177.
Direct Link  |  

23:  Knapp, M.L. and P.D. Mayne, 1987. Development of an automated kinetic Jaffe method designed to minimise bilirubin interference in plasma creatinine assays. Clin. Chim. Acta, 168: 239-246.

24:  Leiper, J., J.S. Maria, A. Chubb, R.J. MacAllister, I.G. Charles, G.S. Whitley and P. Vallance, 1999. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem. J., 343: 209-214.
PubMed  |  

25:  Lin, K., A. Ito, T. Asagami, P.S. Tsao and S. Adimoolam et al., 2002. Impaired nitric oxide synthase pathway in diabetes mellitus: Role of asymmetric dimethylarginine and dimethylargininehydrolase. Circulation, 106: 987-992.
CrossRef  |  

26:  Lokhande, P.D., B.S. Kuchekar, A.R. Chabukswar and S.C. Jagdale, 2006. Nitric oxide: Role in biological system. Asian J. Biochem., 1: 1-17.
CrossRef  |  Direct Link  |  

27:  MacAllister, J., M. Rambausek, P. Vallance, D. Williams, K.H. Hoffmann and E. Ritz, 1996. Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol. Dial. Transplant., 11: 2449-2452.
Direct Link  |  

28:  McGrowder, D., D. Ragoobirsingh and P. Brown, 2006. Therapeutic uses of nitric oxide-donating drugs in the treatment of cardiovascular diseases. Int. J. Pharmacol., 2: 366-373.
CrossRef  |  Direct Link  |  

29:  Meiattini, F., L. Prencipe, F. Bardelli, G. Giannini and P. Tarli, 1978. The 4-hydroxybenzoate/4-aminophenazone chromogenic system used in the enzymic determination of serum cholesterol. Clin. Chem., 24: 2161-2165.
Direct Link  |  

30:  Mittermayer, F., G. Schaller, J. Pleiner, A. Vychytil, G. Sunder-Plassmann, W.H. Horl and M. Wolzt, 2005. Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients. J. Am. Soc. Nephrol., 16: 1832-1838.
CrossRef  |  

31:  Miyazaki, H., H. Matsuoka, J. Cooke, M. Usui, S. Ueda, S. Okuda and T. Imaizumi, 1999. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis. Circulation, 99: 1141-1146.
Direct Link  |  

32:  Murray-Rust, J., J. Leiper, M. McAlister, J. Phelan and S. Tilley, 2001. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat. Struct. Biol., 8: 679-683.
CrossRef  |  Direct Link  |  

33:  Najbauer, J., B. Johnson, A. Young and D.W. Aswad, 1993. Peptides with sequences similar to glycine, arginine rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J. Bio. Chem., 268: 10501-10509.
Direct Link  |  

34:  Nijveldt, R.J., P.A.M. Van Leeuwen, C. Van Guldener, C.D.A. Stehouwer, J.A. Rauwerda and T. Teerlink, 2002. Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans. Nephrol. Dialy Transplant., 17: 1999-2002.
PubMed  |  Direct Link  |  

35:  Regitz-Zagrosek, V., E. Lehmkuhl and M.O. Weickert, 2006. Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin. Res. Cardiol., 95: 136-147.
CrossRef  |  Direct Link  |  

36:  Tepel, M., G.M. van der, M. Statz, J. Jankowski and W. Zidek, 2003. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure. Circulation, 107: 992-995.
Direct Link  |  

37:  Tran, C., M. Fox, P. Vallance and J. Leiper, 2000. Chromosomal localization, gene structure and expression pattern of DDAH1: Comparison with DDAH2 and implications for evolutionary origins. Genomics, 68: 101-105.
PubMed  |  Direct Link  |  

38:  Teerlink, T., 2005. ADMA metabolism and clearance. Vasc. Med., 10: S73-S81.
CrossRef  |  Direct Link  |  

39:  Vallance, P., A. Leone, A. Calver, J. Collier and S. Moncada, 1992. Accumulation of an endogenous inhibitor of Nitric oxide synthesis in chronic renal failure. Lancet, 339: 572-575.
PubMed  |  

40:  Vallance, P. and J. Leiper, 2004. Cardiovascular biology of the asymmetric dimethylarginine: Dimethylarginine dimethylaminohydrolase pathway. Arterioscler. Thromb. Vasc. Biol., 24: 1023-1030.
Direct Link  |  

41:  Vanholder, R., Z. Massy, A. Argiles, G. Spasovski, F. Verbeke and N. Lameire, 2005. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol. Dial. Transplant., 20: 1048-1056.
PubMed  |  Direct Link  |  

42:  Xiao, S., L. Wagner, R. Schmidt and C. Baylis, 2001. Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease. Kidney Int., 59: 1466-1472.
CrossRef  |  Direct Link  |  

43:  Zinellu, A., S. Sotgia, E. Zinellu, A. Pinna and F. Carta et al., 2007. High-throughput CZE-UV determination of arginine and dimethylated arginines in human plasma. Electrophoresis, 28: 1942-1948.
PubMed  |  

44:  Zoccali, C., F. Benedetto, R. Mass, F. Mallamaci, G. Tripepi, L.S. Malatino and R. Boger, 2002. Asymmetric dimethylarginine, C-reactive protein and carotid intima-media thickness in end-stage renal disease. J. Am. Soc. Nephrol., 13: 490-496.
Direct Link  |  

45:  Zoccali, C., S. Bode-Boger, F. Mallamaci, F. Benedetto and G. Tripepi et al., 2001. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Lancet., 358: 2113-2117.
PubMed  |  Direct Link  |  

46:  Zoungas, S., B. McGrath, P. Branley, G. Peter and K.C. Muske et al. 2006. Cardiovascular morbidity and mortality in the atherosclerosis and folic acid supplementation trial (ASFAST) in chronic renal failure. J. Am. Coll. Cardiol., 47: 1108-1116.
CrossRef  |  Direct Link  |  

47:  Natio, H. and A. Kaplan, 1984. Cholesterol. Clin. Chem., 437: 1194-1206.

48:  Schulze, F., R. Maas, R. Freese, E. Schwedhelm, E. Silberhorn and R.H. Boger, 2005. Determination of a reference value for NG, NG-dimethyl-L-arginine in 500 subjects. Eur. J. Clin. Invest., 35: 622-626.
Direct Link  |  

©  2021 Science Alert. All Rights Reserved